Claisen intermediates

ABSTRACT

A total asymmetric synthesis for producing optically active vitamin E, from 2,5,7,8-tetramethylchroman-2-acetaldehyde including intermediates in this synthesis.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Pat. applicationSer. No. 638,382, Chan et al., filed Dec. 8, 1975, now U.S. Pat. No.4,029,678, which in turn is a continuation-in-part of U.S. Pat.application Ser. No. 544,153, Chan et al., filed Jan. 27, 1975, now U.S.Pat. No. 4,000,169.

This application is related to U.S. Pat. application Ser. No. 417,465filed Nov. 19, 1973, now U.S. Pat. No. 3,947,473, Scott, Parrish andSaucy, which is incorporated herein by reference. This application isalso related to U.S. Pat. application Ser. No. 544,163 filed Jan. 27,1975, Cohen and Saucy, now abandoned and U.S. Pat. application Ser. No.587,570, filed June 17, 1975, Chan and Saucy, now U.S. Pat. No.4,016,178.

BACKGROUND OF THE INVENTION

In the past, optically active α-tocopherol and derivatives thereof whichare the 2R, 4'R, 8'R isomer of compounds of the formula: ##STR1## havebeen prepared through isolation from natural sources such as vegetableoil. This procedure suffers from many drawbacks due to the fact that thetocopherol content of these oils is very small. Therefore, a greatamount of oil must be processed in order to isolate a small amount ofnatural tocopherol. Additionally, the process whereby varioustocopherols are isolated from vegetable oil is extremely cumbersome.

In U.S. Pat. application Ser. No. 417,465, filed Nov. 19, 1973, Scott etal., natural α-tocopherol has been synthesized by reacting via a Wittigreaction a compound of the formula: ##STR2## wherein R taken togetherwith its attached oxygen atom forms an ether or ester protecting groupremovable by hydrogenolysis. (Please note the compound of formulaXXVII-A in U.S. application Ser. No. 417,465, filed Nov. 19, 1973) witha dodecanol of the formula: ##STR3## (Please note compound XLVII-B inU.S. application Ser. No. 417,465). A disadvantage of this process isthat the dodecanol of formula III has been difficult to synthesizeasymmetrically. In the past, this dodecanol has been produced through adegradation of naturally occurring materials such as phytol.

SUMMARY OF THE INVENTION

In accordance with this invention, there is provided another procedurefor asymmetrically synthesizing the optically active compound of formulaI from the compound of formula II without the need for separating anddiscarding any unwanted optical isomer.

The new asymmetric synthesis is achieved in accordance with thisinvention by the discovery that when a compound of the formula: ##STR4##wherein R is as above; one of R₁ and R₂ is hydroxy and the other ishydrogen; with the proviso that when R₁ is hydrogen, the 2-3 double bondhas a trans configuration and when R₁ is hydroxy, the 2-3 double bondhas a cis configuration; is subjected to Claisen rearrangement, anoptically active compound of the formula: ##STR5## wherein R is asabove; R₆ is lower alkoxy, ##STR6## R₇, R₈ and R₉ are lower alkyl; isformed which can be directly converted into the optically activecompound of formula I.

DETAILED DESCRIPTION OF THE INVENTION

The numbering of the chain in formula I, above, is shown for the purposeof convenience.

As used throughout the application, the term "lower alkyl" comprehendsboth straight and branched chain saturated hydrocarbon groups containingfrom 1 to 7 carbon atoms such as methyl, ethyl, propyl, isopropyl, etc.As used throughout this application, the term "halogen" includes allfour halogens, such as bromine, chlorine, fluorine and iodine. The term"alkali metal" includes sodium, potassium, lithium, etc.

When the term "cis" is utilized in this application, it designates thatthe two largest substituents attached across the double bond are on thesame side of the double bond. The term "trans" as utilized in thisapplication, designates that the largest substituents attached acrossthe double bond are on opposite sides of the double bond.

In the pictorial representation of the compounds given throughout thisapplication, a ( ) tapered line indicates a substituent which is pointedout of the plane of the paper towards the reader.

The term "lower alkoxy" as used throughout the specification denoteslower alkoxy groups containing from 1 to 7 carbon atoms such as methoxy,ethoxy, propoxy, isopropoxy, etc. The term "lower alkanoyl" as usedthroughout the specification denotes lower alkanoyl groups containingfrom 2 to 6 carbon atoms such as acetyl or propionyl.

In accordance with this invention, the compound of formula II isconverted to the compound of formula V via the following intermediates:##STR7## wherein R and R₆ are as above; M is an alkali metal; R₃ is aradical derived from an aromatic carboxylic acid by removal of thehydroxy moiety of the carboxylic acid group; R₅ is hydrogen, lower##STR8## R₆, R₇, R₈ and R₉ are as above; designates that the double bondhas a cis configuration and designates that the double bond has a transconfiguration.

In the first step of this invention, the compound of the formula:##STR9## is converted to the compound of formula VII by reacting thecompound of formula I with a compound of the formula:

    CH.sub.3 --C.tbd.C--MgX                                    XIII

wherein X is a halogen; via a Grignard reaction. Any of the conditionsconventional in Grignard reactions can be utilized in carrying out thisreaction.

The compound of formula VII can be separated into its diastereoisomersi.e., the compounds of formula VII-A and VII-B by fractionalcrystallization. Any of the conventional methods and techniques offractional crystallization can be utilized to carry out this separation.

On the other hand, the compound of formula VII can be separated into itsdiastereoisomers, i.e., the compound of formula VII-A and VII-B, throughthe reaction of the compound of formula VII with an aromatic carboxylicacid to form a crystallizable ester followed by fractionalcrystallization. The formation of the esters of formula VIII-A andVIII-B is carried out by conventional means such as by reaction with areactive derivative of an aromatic carboxylic acid such as3,5-dinitrobenzoic acid, p-nitrobenzoic acid or benzoic acid. The estersof formula VIII-A and VIII-B are separated by fractionalcrystallization. Any conventional method of fractional crystallizationcan be utilized.

The compound of formula VII-A and VII-B can be obtained from thecompounds of formula VIII-A and VIII-B by alkaline hydrolysis. Anyconventional method of alkaline hydrolysis can be utilized to effectthis conversion.

The compounds of formula VIII-A and VIII-B are converted into thecompounds of the formula VII-A and VII-B respectively. This conversionis generally carried out by ester hydrolysis. Any conventional method ofester hydrolysis can be utilized to carry out this conversion. Apreferred method is carrying out this reaction in the presence of a basesuch as an alkali metal hydroxide base in an aqueous medium.

The compound of formula VII-A is converted to the compound of theformula IX-A by hydrogenation in the presence of a selectivehydrogenation catalyst. Any conventional catalyst which selectivelyreduces only the triple bond (acetylene linkage) to a double bond can beutilized in carrying out this conversion. Among the preferred selectivehydrogenation catalysts are the palladium catalysts which contain adeactivating material such as lead, lead oxide or sulfur. Among thepreferred selective hydrogenation catalysts are included thepalladium-lead catalysts of the type disclosed in Helvetica ChemicaActa., 35, pg. 446 (1952) and U.S. Pat. No. 2,681,938 - Lindlar. Incarrying out this hydrogenation, temperature is not critical and thisrection can be carried out at room temperature. On the other hand,elevated or reduced temperatures can be utilized. Generally, thisreaction is carried out in an inert organic solvent. Any conventionalinert organic solvent can be utilized such as n-hexane, ethyl acetate,toluene, petroleum ether or methanol. The selective hydrogenation of acompound of the formula VII-A utilizing a selective hydrogenationcatalyst produces a cis configuration across the double bond formedthereby. Therefore, the subjection of a compound of the formula VII-A tocatalytic hydrogenation produces a compound of the formula IX-A wherethe double bond formed by the selective hydrogenation has a cisconfiguration.

In accordance with this invention, the compound of formula VII-B isconverted to the compound of formula IX-B by chemical reduction witheither sodium in liquid ammonia or an aluminum hydride reducing agent.The chemical reduction of the compound of formula VII-B reduces thetriple bond to a double bond which has a trans configuration. Hence, thecompound of formula IX-B is formed by this chemical reduction with thedouble bond having a trans configuration. Where the reduction is carriedout utilizing sodium in liquid ammonia, any of the conditionsconventional in this type of reduction can be utilized. Generally, thisreaction is carried out at a temperature of from about -30° C. to -80°C. In this reduction, the liquid ammonia can be utilized as the reactionmedium. On the other hand, a co-solvent can be present in the reactionmedium along with liquid ammonia. As the co-solvents, any conventionalinert organic solvent which is in liquid form at the temperature of thereaction can be utilized. Among the preferred inert organic solvents areincluded ether solvents such as diethyl ether, tetrahydrofuran, etc. Onthe other hand, the reduction can be carried out by treating thecompound of formula VII-B with an aluminum hydride reducing agent. Anyconventional aluminum hydride reducing agent can be utilized to carryout this reduction. Among the preferred reducing agents are the alkylaluminum hydrides reducing agents such as diisobutyl aluminum hydride,diisoamyl aluminum hydride, etc. as well as sodiumbis-[2-methoxyethoxy]-aluminum hydride. The reduction with an aluminumhydride reducing agent is carried out in an inert organic solventmedium. Any conventional inert organic solvent medium can be utilizedfor carrying out this reaction. Among the preferred inert organicsolvents are included tetrahydrofuran, pentane, dioxane, diethylether,hexane, toluene, benzene or xylene. Generally, temperatures of fromabout -120° C. to about 140° C. are utilized in carrying out thisreduction reaction.

In accordance with this invention, when the compound of formula IX-A orIX-B is subjected to Claisen rearrangement, the compound of formula V isproduced. In accordance with this invention, it has been found that bothof the compounds of formula IX-A and IX-B undergo Claisen rearrangementto produce the compound of formula V. The compound of formula IX-A isconverted to the compound of formula V via an intermediate of theformula XI-A and the compound of formula IX-B is converted to thecompound of formula V via an intermediate of the formula XI-B. Any ofthe conditions conventional in Claisen rearrangement can be utilized incarrying out the conversion of either the compound formed by thecompound of the formula IX-A or IX-B to a compound of the formula V. Itis known that Claisen rearrangement occur asymmetrically. See Hill etal., J. Org. Chem., Vol. 37, No. 32, 1972, pages 3737-3740, as well asSucrow et al., Chem. Ber., 104, 3689-3703 (1971), and Sucrow andRichter, Chem. Ber., 104, 3679-3688 (1971). However, in the substratesutilized as starting materials in the Claisen rearrangements disclosedby Hill, asymmetric induction depends upon the presence of the opticallyactive asymmetric carbon atom in the starting material. On the otherhand, in accordance with this invention, in order to obtain byasymmetric induction through the Claisen rearrangement the desiredisomer which can be converted to optically active natural vitamin E,both the proper optical configuration about the asymmetric carbon atomand the proper geometric configuration about the double bond must bepresent in the starting material. If the compound of the formula IX-A orIX-B is utilized in the form of a mixture of optical isomers orgeometric isomers or both, one will not obtain the proper asymmetricinduction through the Claisen rearrangement reaction to produce theintermediate of formula V which can be converted directly to opticallyactive natural vitamin E.

The compounds of formula IX-A and IX-B are converted via the Claisenreaction to the compound of formula V via the intermediates in theformula of XI-A and XI-B. In carrying out this reaction, any of theconditions conventionally utilized in Claisen type rearrangementreaction such as described in the above publications can be utilized. Inaccordance with the preferred embodiment of this invention, the Claisenrearrangement is carried out by reacting the compounds of formula IX-Aor IX-B with any one of the following reactants: ##STR10## wherein R₇and R₈ are as above, and R₁₀ is lower alkyl, and X is halogen.

The compound of formula V where R₆ is hydrogen can be formed by reactingeither the compound of formula IX-A or IX-B with the vinyl ether offormula XV-A via a Claisen rearrangement reaction. Any of the conditionsconventional in carrying out a Claisen rearrangement with a vinyl ethercan be utilized in carrying out this reaction. Where the compound offormula IX-A is utilized, the compound of formula XI-A where R₅ ishydrogen is formed as an intermediate. On the other hand, where thecompound of formula IX-B is utilized as the starting material, thecompound of the formula XI-B where R₅ is hydrogen is formed as anintermediate. In converting the compound of formula IX-A and IX-B to thecompound of formula XI-A and XI-B respectively, the compound of formulaIX-A or IX-B is first reacted with the vinyl ether of formula XV-A. Inreacting either the compound of the formula IX-A or IX-B with thecompound of formula XV-A to form the compound of formula XI-A and XI-Bwhere R₅ is hydrogen, temperatures of from about 40° C. to 150° C. aregenerally utilized. This reaction takes place in the presence of an acidcatalyst. Any conventional acid catalyst can be utilized. Among thepreferred acid catalysts are the inorganic acids such as phosphoric acidand the hydrohalic acids as well as acid salts such as mercuric acetate.On the other hand, conventional organic acid catalysts such as p-toluenesulfonic acid and p-nitrophenol can be utilized. This reaction can becarried out in an inert organic solvent. Any conventional inert organicsolvent having a boiling point of greater than 40° C. can be utilized.Among the preferred solvents are the high boiling hydrocarbon solventssuch as benzene, toluene, xylene, heptane, as well as ether solventssuch as dimethoxyethane, diethylene glycol-dimethyl ether and dioxane.The compound of formula XI-A or XI-B where R₅ is hydrogen can beconverted to the compound of formula V where R₆ is hydrogen by heatingto a temperature of from 80° C. to 200° C. This reaction is carried outin the absence of any catalyst. However, the same solvent mediumutilized for forming the compounds of formulas XI-A or XI-B can beutilized in carrying out this reaction.

On the other hand, the compounds of formula IX-A and IX-B can beconverted to the compound of formula V utilizing the orthoacetate offormula XV-B. In carrying out this reaction, any of the conditionsconventionally used in Claisen rearrangements with this orthoacetate canbe utilized. Where the compound of formula IX-A is utilized, thecompound of formula XI-A where R₅ is lower alkoxy forms as anintermediate. On the other hand, where the compound of formula IX-B isutilized, the compound of formula XI-B forms as an intermediate. Underthe conditions of this reaction, the compound of formula XI-A and thecompound of formulw XI-B where R₅ is lower alkoxy rearrangesinstantaneously to produce the compound of the formula V where R₆ islower alkoxy. In carrying out this reaction, temperatures of from 140°C. are generally utilized. This reaction is carried out in the presenceof excess of the orthoacetate of formula XV-B. This is true since theorthoacetate can be utilized as the solvent medium. On the other hand,the reaction can take place in an inert organic solvent, generally thosesolvents having a boiling point of greater than 140° C. are preferred.Generally it is preferred to carry out this reaction in the presence ofa lower alkanoic acid. If desired, the lower alkanoic acid is present inmolar amounts of from about 1% to 10% per mole of the compound offormula IX-A or IX-B utilized as the starting material.

Where it is desired to produce the compound of formula V where R₆ is##STR11## the compounds of formula IX-A and IX-B are first converted tothe compounds of formula X-A and X-B respectively via acetylation withan acetic acid or reactive derivatives thereof. Any conventional methodof esterifying a hydroxy group with an acetyl group can be utilized tocarry out this conversion. Among the preferred methods is to react thecompound of formula X-A or X-B with a reactive derivative of an aceticacid such as a halide derivative or an anhydride derivative. Thecompounds of formula X-A and X-B in their enolate form are then reactedwith a compound of the formula XV-E to form the compound of the formulaV via a Claisen reaction. The enolates of the compound of formula X-Aand X-B which are the compounds of formula X-A₁ and X-B₁ are produced byreacting the compounds of formula X-A and X-B respectively with analkali metal alkyl amide base. Any conventional alkali metal alkyl amidecan be utilized. The alkyl moiety can be a lower alkyl or cycloalkylmoiety which contains from 5 to 7 carbon atoms. Among the preferredbases are lithium isopropyl cyclohexyl amide and lithiumdiisopropylamide. Upon reaction of the enolate of formula X-A₁ and X-B₁with the silyl halide of formul XV-E, compounds of the formula XI-A orXI-B form, where R₅ is ##STR12## as intermediates. This reaction takesplace utilizing the conditions conventional in Claisen type reactionswith alkyl silyl halides. Generally, the enolates of formula X-A₁ orX-B₁ are reacted with the silyl halide in an inert organic solventmedium at a temperature of from -10° C. to -110° C. In carrying out thisreaction, any conventional inert organic solvent which will not freezeat the reaction temperature can be utilized. Among the preferredsolvents are tetrahydrofuran and diethyl ether.

The compounds of formula XI-A and XI-B where R₅ is ##STR13## areconverted to the corresponding compound of formula V by warming eitherthe compound of formula XI-A or XI-B in the reaction mixture in whichthey were formed to a temperature of from 0° to 40° C. Therefore, inaccordance with this invention, there is no need to isolate thecompounds of formula XI-A and XI-B from their reaction mixture. Thereaction mixture containing the compounds of formula XI-A and XI-B canbe warmed to a temperature of from 0° to 40° C. to form the compound offormula V. On the other hand, the compound of formula XI-A and XI-B canbe isolated from the reaction mixture before warming has commenced.

Where it is desired to produce the compound of formula V where R₆ is##STR14## the compounds of formula IX-A and IX-B are converted to thecompound of formula XI-A and XI-B where R₅ is ##STR15## by conventionalClaisen reaction utilizing conditions conventional in Claisen reactionswith amides of either formulas XV-C or XV-D or mixtures thereof. In thisreaction, the compounds of formula XI-B and XI-A where R₅ is ##STR16##form as intermediates. This reaction is instantaneously converted underthe conditions of the reaction to the compound of formula V. Thisreaction is carried out by reacting compounds of formula IX-A and IX-Bwith a compound of the formula XV-C or XV-D or mixtures thereof. Thisreaction is carried out at temperatures of from 120° C. to 250° C. in aninert organic solvent. Any conventional inert organic solvent can beutilized to carry out this reaction with high boiling solvents, i.e.,solvents being above 120° C. being preferably utilized. Among theconventional inert organic solvents are included xylene and diglyme.

Where R₆ in the compound of formula V is other than hydrogen, thecompound of formula V can be converted to the compound of the formula##STR17## wherein R is as above by hydrolysis by hydrolyzing the esteror amide group. Any conventional method of ester or amide hydrolysis canbe utilized to affect this conversion. The silyl esters are alsohydrolyzed to the compound of formula VI by conventional means. On theother hand, where R₆ in the compound of formula V is hydrogen, thealdehyde can be converted to the compound of the formula VI by oxidizingwith a conventional oxidizing agent.

Any of the conventional oxidizing agents can be utilized. Among thepreferred oxidizing agents are silver oxide and chromic oxide. Any ofthe conditions conventional in utilizing these oxidizing agents can beutilized to convert the aldehyde of formula V to the compound of formulaVI.

In the next step of the process of this invention, the compound offormula VI is esterified with an esterification agent such as a reactivederivative of a lower alkanol to produce a compound of the formula##STR18## where R is as above and R' is lower alkyl.

The compound of formula V can be hydrogenated utilizing a metalhydrogenation catalyst to produce a compound of the formula ##STR19##where R and R' are as above. In this hydrogenation care should beutilized so that no more than one mole of hydrogen is utilized per moleof the compound XVI to prevent hydrogenation of the --OR group to --OH.

Any conventional hydrogenation procedure and metal hydrogenationcatalyst can be utilized to carry out this procedure. Among theconventional metal hydrogenation catalysts are included palladium andplatinum and Raney nickel.

The compound of formula XVI is next converted to a compound of theformula ##STR20## where R is as above by alkaline or acid hydrolysis.Any conventional method of hydrolyzing an ester group by acid oralkaline hydrolysis can be utilized to carry out this procedure.

The compound of formula XVII is converted to the compound of the formula##STR21## where R is as above by reduction.

The compound of formula XVII can be converted into the compound of theformula XVIII by first reducing the compound of formula XVII to thealcohol of formula XVIII. This reduction can be carried out by utilizingan aluminum hydride reducing agent. In utilizing an aluminum hydridereducing agent, any conventional aluminum hydride reducing agent can beutilized. Among the aluminum hydride reducing agents which can beutilized are included lithium aluminum hydride, sodium aluminum hydride,diisobutyl aluminum hydride, diisopropyl aluminum hydride, and sodiumbis[2-methoxyethoxy]-aluminum hydride. This reduction is carried out inan inert organic solvent medium. Any conventional inert organic solventcan be utilized in carrying out this reaction. Among the preferred inertorganic solvents are included tetrahydrofuran, dioxane, diethyl ether,hexane, toluene, benzene or xylene. This reaction can be carried out atroom temperature, i.e., 25° C., and atmospheric pressure. On the otherhand, reduced or elevated temperatures can be utilized, i.e., from -30°C. to about 140° C., with temperatures of from 25° C to 60° C. beingpreferred.

The compound of formula XVIII is next converted to the compound of theformula ##STR22## wherein R is as above and OR₁₂ is a leaving group.

The compound of formula XIX is reacted with a compound of the formula##STR23## wherein X is halogen to form a compound of the formula##STR24## wherein R is as above.

The compound of formula XIX can be prepared from the compound of formulaXVIII by converting the free hydroxy group in the compound of formulaXVIII to a leaving group. Any conventional method of converting ahydroxy group to a leaving group can be utilized. Among the preferredmethods is to react the compound of formula XVIII with an aryl sulfonylhalide such as naphthylsulfonyl halide, p-toluene sulfonyl halide, etc.or a lower alkyl sulfonyl halide such as methylsulfonyl halide in thepresence of an organic amine such as pyridine, triethyl amine, etc.

In the compound of formula XIX, OR₁₂ can be any conventional leavinggroup. Among the preferred leaving groups formed by --OR₁₂ are alkylsulfonyloxy such as methylsulfonyloxy, arylsulfonyloxy, such asp-toluenesulfonyloxy, naphthylsulfonyloxy, etc.

The compounds of formulas XIX and XX are reacted to form the compound offormula XXI in the presence of a di(alkali metal)tetrahalocuprateutilizing the procedure disclosed by Fouquet and Schlosser on pages 82and 83 of Angew. Chem. Internat. Edit., Volume 13 (1974). In theprocedure disclosed by Fouquet and Schlosser, carbon to carbon linkageof hydrocarbons is carried out through the reaction of a magnesiumhalide with a sulfonyl ester. In this reaction, any conventionaldi(alkali metal)tetrahalocuprate can be utilized with dilithiumtetrachlorocuprate being preferred. Generally, this reaction is carriedout in the presence of an ether solvent. Any conventional inert organicether solvent can be utilized. Among the preferred solvents are includedtetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, diglyme, etc.

The compound of formula XXI can be converted to the compound of formulaI by hydrogenation in the presence of a hydrogenation catalyst such aspalladium, platinum, Raney nickel, etc. Any conventional method ofhydrogenation can be utilized to make this conversion.

The compound of formula XX and its method of preparation is disclosed inSer. No. 544,163 filed Jan. 27, 1973, Cohen and Saucy. Note the compoundof formula IX in Ser. No. 544,163 where n is O, R₅ is --CH₂ MgX and Aand B are hydrogen. Also note Examples 10 and 12 of Ser. No. 544,163.The disclosure of this application, Ser. No. 544,163, filed Jan. 27,1973, is incorporated by reference.

As used herein, the term "aryl" signifies mononuclear aromatichydrocarbon groups such as phenyl, tolyl, etc. which can beunsubstituted or substituted in one or more positions with a loweralkylenedioxy, a halogen, a nitro, a lower alky or a lower alkoxysubstituent, and polynuclear aryl groups such as naphthyl, anthryl,phenanthryl, azulyl, etc., which can be unsubstituted or substitutedwith one or more of the aforementioned groups. The preferred aryl groupsare the substituted and unsubstituted mononuclear aryl groups,particularly phenyl. The term "aryl lower alkyl" comprehends groupswherein aryl and lower alkyl are as defined above, particularly benzyl.The term "aroic acid" comprehends acids wherein the aryl group isdefined as above. The preferred aroic acid is benzoic acid. The term"ether protecting group removable by hydrogenolysis" designates anyether which, upon hydrogenolysis yields the hydroxy group. A suitableether protecting group is arylmethyl ethers such as benzyl, benzhydrylor trityl ethers.

The preferred ethers which are removable by hydrogenolysis are the arylmethyl esters such as benzyl or substituted benzyl ethers. Thehydrogenolysis can be carried out by hydrogenation in the presence of asuitable hydrogenation catalyst. Any conventional method ofhydrogenation can be utilized in carrying out this procedure. Anyconventional hydrogenation catalyst such as palladium or platinum can beutilized.

The following examples are illustrative but not limitative of theinvention. All temperatures are in degrees Centigrade and the ether isdiethyl ether. The term "5% Pd-C" designates a carbon catalystcontaining 5% by weight palladium and 95% by weight carbon. The term"THF" designates tetrahydrofuran and the term "HMDA" describedhexamethylenephosphoramide. The term "concentrated aqueous hydrochloricacid" designates 10N hydrochloric acid. The term "Kugelrohr" designatesevaporation distillation. The term "Lindlar catalyst" designates acatalyst prepared from palladium, calcium carbonate and lead acetate asdescribed in Organic Synthesis Collective, Vol. 5, pages 880-883 (1973).

EXAMPLE 1 Preparation of2(S)-[2(R)-hydroxy-3-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxychromanand2(S)-[2(S)-hydroxy-3-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxychroman

To an excess of propynyl magnesium bromide (approximately 2.5equivalents) in 1.0 liter of dry ether was added 64 g. (0.189 mol) of(S)-6-benzyloxy-2,5,7,8-tetramethylchrom-2-acetaldehyde in 1.0 liter ofdry ether, at 0°-4° C. with mechanical stirring. When addition wascomplete, the reaction mixture was further stirred at 0° C. for 1/2 hourand then 25° C. for 1/2 hour. The reaction mixture was poured in smallportions into 500 ml. of saturated aqueous NH₄ Cl solution. It wasextracted with diethyl ether (4 × 250 ml.). The combined ether extractwas washed with water (3 × 200 ml.), dried over MgSO₄ and concentratedat reduced pressure. Crystallization of the crude product from diethylether-petroleum ether (30°-60° C.) yielded 27.5 g. of2(S)-[2(R)-hydroxy-3-pentynyl]2,5,7,8-tetramethyl-6-benzyloxychroman,m.p. 89°-91° C.

The mother liquor from the above was concentrated to dryness andcrystallized from ether-hexane to give 5.01 g. of2(S)-[2(S)-hydroxy-3-pentynyl]2,5,7,8-tetramethyl-6-benzyloxychroman aswhite crystals, m.p. 74°-76° C. [α]_(D) ²⁵ -42.01°.

EXAMPLE 2 Preparation of2(S)-[2(R)-hydroxy-3(E)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychroman

To a solution of 5.0 g. (13.32 mmol) of2(S)-[2(R)-hydroxy-3-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxy-chromanin 50 ml. of dry ether was carefully added 4.06 ml. of sodiumbis(2-methoxyethoxy)-aluminum hydride (29 mg. - atm. of hydrogen) in 10ml. of dry ether. The resulting solution was refluxed under argon for 17hours. The solution was cooled in an ice bath and 10% by volumn aqueousH₂ SO₄ solution (100 ml.) was carefully added. It was filtered, washedwith ether and water. The aqueous phase was again extracted with ether(3 × 100 ml.). The combined ether phase was washed with saturatedaqueous NaHCO₃ solution (3 × 50 ml.) and water (3 × 50 ml.) and driedover MgSO₄. Evaporation of ether to dryness at reduced pressure yielded5.206 g. of crude product which was crystallized from petroleum ether(b.p. 30°-60° C.) to give 4.23 g. of2(S)-[2(R)-hydroxy-3(E)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychromanas white needles, m.p. 68°-70° C. [α]_(D) ²⁵ -24.02° (CHCl₃).

EXAMPLE 3 Preparation of2(S)-[2(S)-hydroxy-3(Z)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychroman

2.5 g. of2(S)-[2(S)-hydroxy-3-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxychromanand 0.25 g. of Lindlar catalyst in 15 ml. of ethyl acetate-hexane (2 = 1parts by volume) containing 0.1 ml. of quinoline was hydrogenated at 25°C. and atmospheric pressure. The catalyst was filtered off and washedwith ethyl acetate. The ethyl acetate solution was washed with 1.0 Naqueous HCl (3 × 50 ml.), water (3 × 50 ml.) and dried over MgSO₄ andconcentrated in vacuo to give 2.508 g. of crude product. Crystallizationof this material from pentane yielded 2.053 g. of2(S)-[2(S)-hydroxy-3(Z)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychromanas white crystals, m.p. 84°-86° C. [α]_(D) ²⁵ -30.57° (CHCl₃).

EXAMPLE 4 Preparation of6-[2(S)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(R)-methyl-4(E)-hexenoicacid, ethyl ester

To 4.42 g. (1.16 mmol) of2(S)-[2(R)-hydroxy-3(E)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychromanwas added 13.10 g. (8.12 mmol) of triethylortho acetate and 85.5 mg.(0.116 mmol) of propionic acid. The solution was degassed with argon andrefluxed for 4.0 hours while the ethanol formed was distilled off. Theexcess of reagent was removed in vacuo and the oily crude product waspassed over 125 g. of silica gel. Elution with 1:4 parts by volumediethyl ether-petroleum ether (30°-60°) afforded 4.86 g. (92% yield) of6-[2(S)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(R)-methyl-4(E)-hexenoicacid, ethyl ester as colorless oil, [α]_(D) ²⁵ +0.91° (c 5.0475, CHCl₃).

EXAMPLE 5

By the procedure of Example 4, 1.05 g. of6-[2(S)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(R)-methyl-4(E)-hexanoicacid, ethyl ester was prepared from 1.0 g. of2(S)-[2(S)-hydroxy-3(Z)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychroman,3.0 g. of triethylortho acetate and 19.5 mg. of propionic acid.

EXAMPLE 6 Preparation of6-[2(S)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(R)-methyl-4(E)-hexenoicacid

A solution of 2.0 g. (0.44 mmol) of6-[2(S)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(R)-methyl-4(E)-hexenoicacid, ethyl ester in 7 ml. of methanol and 2 ml. of 6.0 N NaOH wasrefluxed for 2.0 hours. The solution was diluted with water (ca. 150ml.) and extracted with ether (2 × 30 ml.). The aqueous alkaline phasewas cooled in an ice bath and then acidified with concentratedhydrochloric acid. It was extracted with ether (5 × 50 ml.). Thecombined ether extract was washed twice with saturated aqueous NH₄ Cland dried over MgSO₄. Evaporation of ether to dryness in vacuo yielded1.57 g. of6-[2(S)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(R)-methyl-4(E)-hexenoicacid, as colorless oil (84% yield), [α]_(D) ²⁵ -2.73°.

EXAMPLE 7 Preparation of6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methylhexanoicacid, ethyl ester

3.36 g. of6-[2(S)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(R)-methyl-4(E)-hexenoicacid, ethyl ester and 350 mg. of 5% palladium on charcoal washydrogenated in 20 ml. of ethyl acetate at 23° and one atmosphere untilone equivalent of hydrogen was consumed. The catalyst was filtered offand was washed with ethyl acetate. Evaporation of solvent to dryness invacuo gave 3.07 g. of6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methyl-hexanoicacid, ethyl ester as colorless oil, [α]_(D) ²⁵ -0.22° (c 4.135, CHCl₃).

EXAMPLE 8 Preparation of6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methylhexanoicacid, ethyl ester

6-[2(S)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(R)-methyl-4(E)-hexenoicacid, ethyl ester (1.0 g., 2.2 mmol) was hydrogenated over 200 mg. ofRaney nickel in ethyl acetate (25 ml.) at 25° C., 30 p.s.i.g. for 4.0hours. The Raney nickel was filtered off and washed well with ethylacetate. Evaporation of ethyl acetate to dryness in vacuo gave 1.005 g.of colorless oil. This was dissolved in dimethylformamide (10 ml.) andtreated with 532 mg. (3.8 mmol) of anhydrous potassium carbonate and 435mg. (3.8 mmol) of benzyl chloride at 25° for 60 hours. The reactionmixture was diluted with water (150 ml.) and extracted with ether (3 ×70 ml.). The combined ether extract was washed with water (3 × 30 ml.),once with saturated brine (50 ml.) and dried over anhydrous MgSO₄.Evaporation of ether to dryness in vacuo yielded 930 mg. of crudeproduct which was purified by column chromatography on 40 g. of silicagel. Elution with ether-petroleum ether (3:7) gave 650 mg. of pure6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methylhexanoicacid, ethyl ester.

EXAMPLE 9 Preparation of6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methylhexanoicacid

600 Mg. (1.33 mmol) of6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methylhexanoicacid, ethyl ester was refluxed for 2.0 hours in 10 ml. of methanol and 2ml. of 6N NaOH. The reaction mixture was cooled to room temperature anddiluted with water and washed with ether. The alkaline aqueous phase wascooled in an ice bath and acidified with concentrated hydrochloric acid.It was then extracted with ether. The ether extracts were combined,washed with three portions of saturated NH₄ Cl solution and dried overanhydrous MgSO₄. Evaporation of the ether to dryness in vacuo gave theoily crude acid, which was quickly filtered through a column of silicagel (10 g.) and elution with CHCl₃ yielded 510 mg. (90% yield) of6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methylhexanoicacid as colorless oil, [α]_(D) ²⁵ -1.66° (c 1.9288, CHCl₃).

EXAMPLE 10 Preparation of6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methylhexanol

To a solution of 2.20 g. (4.85 mmol) of6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methylhexanoicacid, ethyl ester in 20 ml. of dry ether was slowly added 0.81 ml. (5.82mmol) of sodium bis-(2-methoxyethoxy)aluminum hydride (70% in benzene)in 2 ml. of dry ether. The solution was refluxed for 1.0 hour. Anadditional 1 ml. of sodium bis-(2-methoxyethoxy) aluminum hydride wasadded again and it was refluxed for 2.0 hours more. The reaction mixturewas cooled to 0° C. and excess of hydride was destroyed by carefullyadding 10 ml. of 1.0 N H₂ SO₄ followed by 100 ml. of water. Theprecipitate was filtered off and washed well with ether. The aqueousphase was separated and extracted with ether (3 × 60 ml.). The combinedether extract was washed with water (2 × 30 ml.), saturated brine (30ml.) and dried over anhydrous MgSO₄. Evaporation of ether to dryness invacuo gave 2.175 g. of crude product which was chromatographed on 100 g.of silica gel. Elution with 3-7 parts by volume ether-petroleum etherafforded 1.55 g. (78% yield) of6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methylhexanolas a colorless oil, [α]_(D) ²⁵ -0.59° (c 1.010, CHCl₃).

EXAMPLE 11 Preparation of6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methylhexanolp-toluenesulfonate

To 1.226 g. (2.98 mmol) of6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methylhexanolin 4 ml. of dry pyridine (dried and distilled over barium oxide) wasadded in portions 1.14 g. (5.96 mmol) of p-toluenesulfonyl chloride at0° C. The resulting solution was stirred at 0° C. for 3.0 hours and thenkept in the refrigerator for 16 hours. The mixture was poured into 100ml. of ice water and acidified with 3N HCl (about 50 ml.). It wasextracted with ether (3 × 70 ml.). The combined ether extract was washedwith water (3 × 30 ml.) and dried over anhydrous potassiumcarbonate-sodium sulfate (ca. 1 = 1). Evaporation of ether to dryness invacuo yielded 1.804 g. of6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methylhexanolp-toluenesulfonate as yellow oil, ms = m/e 564 (M⁺).

EXAMPLE 12 Preparation of (2R,4'R, 8'R)-α-tocopherol benzyl ether

To 195 mg. (8.0 mmol) of powdered magnesium in 3 ml. of dry THF wasadded dropwise 1.24 g. (6.00 mmol) pf 2(R)-6-dimethylheptyl-1-magnesiumbromide (prepared from (R)-1-bromo-2,6-dimethylheptane) in 3 ml. of dryTHF. The reaction mixture was stirred and refluxed under argon for 3.0hours and then at 25° for 1.0 hour. It was then cooled to -78° C. in adry ice-acetone bath and to this solution was added 0.1 ml. of LiCuCl₄,followed by 0.64 g. (1.14 mmol) of6-[2(R)-6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-3(S)-methylhexanolp-toluenesulfonate in 10 ml. of THF. It was stirred at -78° for 10minutes and then allowed to warm to 25° and stirred for 17 hours underargon. The mixture was treated with 5 ml. of 1N aqueous H₂ SO₄ and wasworked up by ether extraction giving 1.026 g. of crude product. Thismaterial was purified by thick layer chromatography on silica gel andelution with ethyl ether-hexane (5 = 95) afforded 406 mg. of(2R,4'R,8'R)-α-tocopherol benzyl ether (69% yield).

EXAMPLE 13 Preparation of (2R,4'R, 8'R)-α-tocopheryl acetate

(2R,4'R,8'R)-α-Tocopherol benzyl ether (326 mg., 0.626 mmol) and 60 mg.of 5% palladium on carbon was hydrogenated in 5 ml. of THF containingtwo drops of concentrated hydrochloric acid at 25° C. and atmosphericpressure for 11/2 hour. The catalyst was filtered off and washed wellwith ethyl acetate. Evaporation of ethyl acetate to dryness at reducedpressure gave 239 mg. of (2R,4'R,8'R)-α-tocopherol as a light yellowoil. This material was treated with 2 ml. of dry pyridine and 2 ml. ofacetic anhydride at 25° for 16 hours. The mixture was poured into icewater (25 ml.) and extracted with chloroform (3 × 50 ml.). The combinedchloroform extract was successfully washed with 1.0 N aqueous HCl (3 ×20 ml.), saturated aqueous NaHCO₃ solution (3 × 20 ml.), water (3 × 20ml.) and dried over anhydrous MgSO₄. Evaporation of solvent to drynessin vacuo gave 250 mg. of crude product. This material was purified bythick layer chromatography on silica gel and elution withether-petroleum ether (1:4) afforded 188 mg. (63.7% from benzyl ether)of pure (2R,4'R,8'R)-α-tocopheryl acetate as a slightly yellow oil,[α]_(D) ²⁵ +2.59°.

We claim:
 1. A compound of the formula ##STR25## wherein R is trityl,benzyl, benzhydryl or lower alkenyl; one of R₁ and R₂ is hydrogen, andthe other is ##STR26## with the proviso that when R₁ is hydrogen, the2-3 double bond has a trans configuration and that when R₁ is other thanhydrogen the 2-3 double bond has a cis configuration.